In work first reported in 2000 and supported entirely by the current grant, we identified the cause of human narcolepsy as a loss of cells containing hypocretin (Hcrt, or orexin). Similar results were reported by the group at Stanford University at the same time. While these discoveries have been a major advance in our understanding of narcolepsy, important questions remain unanswered. Despite the discovery of a link between Hcrt cell loss and narcolepsy, the anatomical bases of several major symptoms of narcolepsy remain unexplained. For example, narcoleptics have disrupted nighttime sleep and an increased incidence of REM sleep behavior disorder, symptoms that appear to be opposite to the sleepiness and cataplexy that are the best known characteristics of narcolepsy. It is likely that other brain systems are altered in narcolepsy either by the process that removes Hcrt cells or by the direct and indirect postsynaptic effects of the loss of these cells. We will look for anatomical clues to the changes occurring in narcolepsy by measuring, in Hcrt KO mice and in human narcoleptics, Hcrt receptor numbers and in the number, size, dendritic fields and morphology of cholinergic, monoaminergic and other cells normally receiving Hcrt axonal projections. We will determine which of these changes can be reversed by Hcrt administration to Hcrt knockout mice. Changes in Hcrt receptors and in the structure of the cells receiving Hcrt projections will determine the effect of Hcrt administration as a treatment for narcolepsy. It is unclear whether narcolepsy without cataplexy is the same disease as narcolepsy with cataplexy. Up to half of all narcoleptics diagnosed according to current nosology do not have cataplexy and have normal levels of Hcrt in the cerebrospinal fluid. We will determine the number, distribution and morphology of Hcrt neurons in these patients. Narcolepsy appears to be the simplest neurodegenerative disease, in terms of the very restricted pathology that seems to underlie it. Analysis of how the loss of only 60,000 Hcrt cells causes the varied symptoms of narcolepsy by altering brain anatomy may well serve as a model for comprehending the symptoms of, and developing treatments for, other neurodegenerative diseases, including Parkinson's disease, which we have recently shown is also accompanied by a loss of Hcrt neurons. PUBLIC HEALTH RELEVANCE This work may help clarify the nature of the processes that cause Hcrt cell loss in narcolepsy. It will also help us better understand the sleep symptoms of narcolepsy and may have general relevance for understanding symptoms that are common in narcolepsy, but that are not restricted to narcoleptics, including depression, daytime sleepiness, insomnia and REM sleep behavior disorder.